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Introduction to disorders of fatty acid oxidation
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The genetically determined disorders of fatty acid oxidation represent a recently rapidly growing group of inborn errors of metabolism. The field, as we know it today, really dates from the discovery in 1982 of medium-chain acyl CoA dehydrogenase (MCAD) deficiency (Chapter 39) [1, 2]. Myopathic carnitine palmitoyl transferase (CPT II) (Chapter 38) deficiency was known for some time earlier, but considered among myopathies not a forerunner of expansive growth of knowledge, and HMG CoA lyase deficiency (Chapter 46) had been described but considered to be an organic acidemia. Multiple acyl CoA dehydrogenase deficiency (Chapter 45) was also known since 1976. The fact that MCAD deficiency turned out to be common, and largely the consequence of a single mutation, has contributed to the current recognition of the importance of this group of disorders. In subsequent years, the rates of discovery of previously unrecognized disorders of fatty acid oxidation was exponential. The advent of diagnosis by tandem mass spectrometry and its application to programs of expanded screening of newborns [3] have opened up this entire population to the prevention of death and disability.
Exploring the contribution of mitochondrial dynamics to multiple acyl-CoA dehydrogenase deficiency-related phenotype
Published in Archives of Physiology and Biochemistry, 2021
Sofia R. Brandão, Rita Ferreira, Hugo Rocha
Among FAOD, multiple acyl-CoA dehydrogenase deficiency (MADD) is one of the screened disorders that present heterogeneous clinical phenotypes (Frerman and Goodman 1985, 2001), being recognized three clinical forms. Two severe neonatal-onset forms: with (type I) and without (type II) congenital abnormalities. The late-onset form (type III) is associated to milder phenotypes (Vockley and Whiteman 2002). In most FAOD, including MADD, the association between the phenotype and the genotype is not straightforward (Gregersen et al.2001, Kompare and Rizzo 2008, Olsen et al.2013). The observed clinical spectrum in MADD patients suggests that other specific molecular and cellular mechanisms may have a key role in MADD pathogenesis, in addition to mutations in the genes associated to this disease (Olsen et al.2003, Grünert 2014). These findings make MADD an interesting model to better understand the molecular mechanisms underlying the pathophysiology associated with MADD and other FAOD.
Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis
Published in Expert Opinion on Orphan Drugs, 2018
Evelina Maines, Giovanni Piccoli, Antonia Pascarella, Francesca Colucci, Alberto B. Burlina
The most common FAODs presenting with hyperammonemia are carnitine uptake deficiency (CUD, OMIM #212140), carnitine acylcarnitine translocase deficiency (CACTD, OMIM #212138), the neonatal and infantile forms of carnitine palmitoyltransferase II deficiency (CPT II deficiency, OMIM #608836, #600649), medium-chain acyl-CoA dehydrogenase deficiency (MCADD, OMIM #201450) and multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM #231680) [80]. While there is the possibility that many patients died without being diagnosed or are symptomatic but undiagnosed, it is also very likely that many undiagnosed individuals with these disorders are asymptomatic. There is considerable evidence that many infants identified by NBS with MCADD remain asymptomatic. Early infancy treatment is not likely the reason. It is therefore probable that many, perhaps most, of the infants identified with MCADD by NBS have a mild and perhaps asymptomatic form of the disorder [81].
A novel ETFDH mutation in an adult patient with late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency
Published in International Journal of Neuroscience, 2018
Min Chen, Jing Peng, Wei Wei, Rui Wang, Hongliang Xu, Hongbo Liu
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty and organic acid metabolism resulting from a deficiency of electron transfer flavoprotein A (ETFA), electron transfer flavoprotein B (ETFB) or ETF dehydrogenase (ETFDH) [1,2]. The symptoms can be mild or severe. The former may only occur in times of stress, and the latter include congenital anomalies, especially of the kidneys and heart. The symptomatology range from milder forms susceptible to decompensation only at times of metabolic stress, to severe forms resulting in congenital anomalies and perinatal death. Pathologically, the lipid accumulations in the liver, heart and renal tubular epithelium are in tissues that use fatty acids as a primary source of energy. Vacuolar myopathy with lipid accumulation also has been reported [3]. Late‑onset MADD is mainly caused by ETFDH mutation that results in misfolding and instability of ETFDH protein [4,5]. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases. Up to now, more than 100 mutations had been reported [6]. The vast majority carried mutations in the ETFDH gene (93.1%) [6]. Three common mutations had been described in the worldwide population: c.250 G > A (p.A84T), c.389 A > T (p.D130V), c.1227A > C (p.L409F) [6]. Three common mutations in the ETFDH gene have been described which are mainly found in the Chinese and Taiwanese population: c.250 G > A (p.A84T), c.770A > G (p.Y257C), c.1227A > C (p.L409F) [7–9]. When it comes to c.814G > A, there was only one report on child ageing 12 months with Rota-virus gastroenteritis, hypoglycaemia and seizures [10]. Herein, we report an adult women presenting lipid deposition disease and hypoglycemia carry compound heterozygous mutation, c.814G > A and c.389A >T in the ETFDH gene.